Abstract Title: Mechanism of Lassa fever virus Z protein in immune suppression and viral virulence Lassa fever virus (LASV) is the most significant arenavirus pathogen that causes endemic and lethal hemorrhagic fever (HF) in humans in West Africa with thousand of death annually. Importation of LASV infection to USA and other Western counties has been repeatedly documented due to increased human travel to and from the endemic countries. Currently there is no vaccine and limited treatment options against LASV. Among LASV-infected individuals, there are significant heterogeneity in disease severity, which ranges from asymptomatic infections to multi-organ failure and death, the reason for which is unknown but may partly be due to the different LASV isolates that show sequence variations up to 32%. Molecular determinants for LASV virulence remain unknown. LASV pathogenesis has not been well understood but is associated with a general host immune suppression that is characterized by the lack of early innate immune responses and the absence of effective adaptive immunity. The long-term goal of our work is to understand the mechanisms of LASV virulence and disease pathogenesis in order to develop the much-needed vaccines and antivirals. We have recently discovered a unique ability of the Z protein of several known pathogenic arenaviruses (including LASV) to inhibit the human RIG-i-like receptors (RLRs) RIG-i and MDA5, which are the intracellular sensors of RNA viruses. We have also obtained preliminary evidence to show that the Z proteins from different LASV isolates vary in their ability to inhibit RLRs. In addition, we show that this Z-mediated RLR binding and inhibition is species specific, which may explain the observed differences in disease pathogenesis in different animal species. We hypothesize that the virus- and host-dependent inhibition of RLRs by LASV Z proteins is a novel virulence determinant and propose the following aims to test this hypothesis. Aim 1: Dissect the molecular mechanism of LASV Z-mediated RLR inhibition. Aim 2: Determine the biological role of LASV Z-mediated RLR inhibition in viral virulence. Aim 3: Investigate the species-specific mechanism of LASV Z-mediated of RLR inhibition. These studies focus on a novel immune suppressive and virulent mechanism mediated by LASV Z protein, which will not only make major impacts on both basic and translational research of arenavirus pathogens, but also provide new knowledge in host-pathogen interactions, host antiviral responses, and viral immune evasion mechanisms.